Ancient DNA Reveals 12,000-Year-Old Case of Rare Genetic Disorder

Researchers from the University of Vienna and Liège University Hospital Centre have identified genetic variants associated with a rare inherited growth disorder in two prehistoric individuals who lived more than 12,000 years ago. Utilizing ancient DNA analysis and modern clinical genetics, the team diagnosed the condition in a mother and daughter buried together in southern Italy. The study, published in the New England Journal of Medicine, demonstrates that paleogenomics can reconstruct ancient population history and diagnose rare genetic diseases in prehistoric individuals.

The discovery stems from a reanalysis of an Upper Paleolithic burial site discovered in 1963 at Grotta del Romito in southern Italy. The burial featured two individuals interred together in an embrace: 'Romito 2,' an adolescent with pronounced limb shortening, previously assumed to be male, and 'Romito 1,' thought to be an adult female. Romito 2 had an estimated height of about 110 cm, consistent with a rare skeletal growth disorder known as acromesomelic dysplasia, though this could not be confirmed solely from bones. Romito 1 was also shorter—about 145 cm—than average for the period. For decades, researchers debated their gender, relationship, and the possibility of a common cause of their short stature.

The team analyzed ancient DNA extracted from the petrous part of the temporal bone of both individuals, a region known for preserving genetic material well. Genetic analysis established a first-degree relationship. The researchers then screened genes associated with skeletal growth and compared the identified variants with modern clinical data. This interdisciplinary approach, combining paleogenomics, clinical genetics, and physical anthropology, involved an international team from the University of Vienna and collaborators in Italy, Portugal, and Belgium.

The analysis revealed that both individuals were female and first-degree relatives, most likely a mother and daughter. In Romito 2, researchers identified a homozygous variant in the NPR2 gene, which is essential for bone growth. This confirmed a diagnosis of acromesomelic dysplasia, Maroteaux type—a very rare inherited disorder characterized by severe short stature and marked shortening of the limbs. Genetic data from Romito 1 indicate that she carried one altered copy of the same gene, a condition associated with milder short stature.

Ron Pinhasi of the University of Vienna, who co-led the study, stated that by applying ancient DNA analysis, specific mutations in prehistoric individuals can now be identified, helping to establish how far back rare genetic conditions existed and potentially uncover previously unknown variants. Daniel Fernandes, first author of the study from the University of Coimbra, noted that identifying both individuals as female and closely related turns this burial into a familial genetic case, with the older woman's milder short stature likely reflecting a heterozygous mutation, showing how the same gene affected members of a prehistoric family differently. Adrian Daly of Liège University Hospital Centre, a co-leader of the study, highlighted that rare genetic diseases are not a modern phenomenon but have been present throughout human history, and understanding their history may help in recognizing such conditions today.

Despite severe physical limitations, Romito 2 survived into adolescence or adulthood, suggesting sustained care within her community. Alfredo Coppa of Sapienza University of Rome, who also co-led the study, suggested that her survival would have required sustained support from her group, including help with food and mobility in a challenging environment.